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PubMed1991

Redox reactive reagents inhibiting and inactivating choline acetyltransferase.

3-Trimethylammoniomethyl catechol and N,N-dimethylepinephrine (catecholine) are redox reactive reagents which possess quaternary ammonium functional groups and the capacity to inhibit or inactivate choline binding macromolecules which mediate cholinergic neuronal function. Earlier studies reported the synthesis of 3-trimethylammoniomethyl catechol and demonstrated its redox-dependent covalent inactivation of the nicotinic acetylcholine receptor (Nickoloff et al., Biochemistry 24, 999-1007 (1985)]. Here we present the synthesis of catecholine and show that both 3-trimethylammoniomethyl catechol and catecholine are weak noncompetitive inhibitors (Ki = 15 +/- 6 and 25 +/- 4 mM, respectively) of choline acetyltransferase (EC 2.3.1.6). Both agents irreversibly inactivate the enzyme.

Animals↗
PubMed1988

Experimental inhibition of reactive gliotic-like changes in astrocytic cultures.

Dibutylcyclic AMP (DiBucAMP) can induce astroblast-containing cultures to form cells which resemble reactive astrocytes observed in vivo. In the present study, myelin- or axolemmal-enriched fractions were assessed for the ability to inhibit (DiBucAMP)-stimulated reactive-like changes in astrocytic cultures. Addition of exogenous myelin- or axolemmal-enriched fractions to DiBcAMP-exposed cultures prevented drug-induced elevation of lactic dehydrogenase (LDH) 2 days after initial addition of the drug and moderated DiBucAMP-induced decreases in the enzyme's activity normally observed 5 days later. The proportion of reactive colonies (i.e., those in which more than 50% of cells are stellate-shape) was significantly lower in cultures exposed to the drug plus myelin or axolemma vs those exposed to DiBucAMP alone. The inhibitory factors in axolemmal fractions were heat sensitive (at 100 degrees C), whereas those in myelin were not. Both fractions were inactivated by trypsin. Whole brain homogenates had no effect on diBucAMP-stimulated changes in culture.

Animals↗
PubMed1991

C-reactive protein inhibits binding of platelet-activating factor to human platelets.

Serum concentration of C-reactive protein (CRP), a prototypical acute-phase protein rises dramatically in response to tissue injury or inflammation. We report here that CRP (1-20 micrograms/ml) inhibited platelet-activating factor (PAF)-induced aggregation of human platelets in time-, and dose-dependent manner. This inhibitory action of CRP was nearly completely removed by treatment with anti CRP antiserum. At higher concentrations (20-100 micrograms/ml), CRP stabilized platelet membrane against the detergent-like effect of beta-deoxy-lysolecithin. Furthermore, CRP (10 micrograms/ml) diminished specific [3H]PAF binding to platelets and displaced previously bound labeled PAF from platelets. These results suggest that by depressing the bioavailability of PAF, CRP may be an important modulator of platelet activation during acute inflammatory reactions.

Antibody Formation↗
PubMed1990

Human C-reactive protein inhibits neutrophil chemotaxis in vitro: possible implications for the adult respiratory distress syndrome.

C-reactive protein (CRP) is an acute-phase protein whose serum concentration can rise dramatically after onset of inflammation. Although the precise physiologic role of elevated CRP is not known, in vitro studies have shown that CRP potentially has both pro- and anti-inflammatory properties. We hypothesized that an elevation in serum CRP may be a mechanism to control acute inflammation by down-regulating some neutrophil functions. Therefore, elevated serum CRP levels in an inflammatory state in the lung, such as the adult respiratory distress syndrome (ARDS), may have a protective effect. We observed that highly purified CRP, at levels greater than 25 micrograms/ml, inhibited both random neutrophil movement and C5a-induced chemotaxis. Neutrophils incubated with CRP showed a dose-dependent diminution of migration toward chemotactic stimuli, with complete inhibition occurring at 100 micrograms/ml. This inhibitory effect of CRP on neutrophil movement was only partially reversed by washing the CRP-treated cells before assaying their chemotactic movement to 1 nmol/L C5a. Next we examined the neutrophil chemotactic activity of serum collected from normal nonsmokers, from patients at high risk for developing ARDS, and patients with ARDS. Both high-risk and ARDS serums has significantly less (p less than 0.001) neutrophil chemotactic activity than serums from normal subjects. In addition, serums from high-risk and ARDS patients had significantly elevated (p less than 0.001) levels of CRP compared with normal subjects. Anti-CRP treatment of ARDS and high-risk serum samples resulted in a significant increase (p less than 0.05) in the neutrophil chemotactic activity. Finally, addition of highly purified CRP to normal serum significantly reduces its neutrophil chemotactic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1996

Synthetic peptides derived from the sequence of human C-reactive protein inhibit the enzymatic activities of human leukocyte elastase and human leukocyte cathepsin G.

Peptides derived from the primary sequence of the acute phase reactant C-reactive protein (CRP) are shown to inhibit in vitro the enzymatic activities of human leukocyte elastase (hLE) and human leukocyte cathepsin G (hCG), which are associated with tissue damage occurring in the course of several chronic inflammatory conditions. CRP-derived peptides were synthesized based on their sequence similarity to domains within the natural inhibitors of hLE and hCG. The octapeptide Val89-Thr-Val-Ala-Pro-Val-His-Ile96 (CRP 89-96) is shown to inhibit hLE and hCG to a larger extent than peptides of similar chain lengths corresponding to the active sites of their natural inhibitors, alpha 1-protease inhibitor and alpha-antichymotrypsin, respectively. Several additional peptides containing this core sequence were synthesized and shown to be inhibitors, in contrast to peptides derived from other regions of CRP as well as the intact protein, which are totally inactive. The inhibitory capability of CRP-derived peptides, which may be generated in vivo by neutrophil-mediated proteolysis as part of a complex regulatory homeostatic mechanism, may now be used as a basis for the design of novel therapeutic substances. The present finding may shed some light on the enigmatic physiological functions of CRP.

C-Reactive Protein↗
PubMed2004

Multiple sclerosis: glatiramer acetate inhibits monocyte reactivity in vitro and in vivo.

It is widely assumed that glatiramer acetate (GA), an approved agent for the immunomodulatory treatment of multiple sclerosis, acts primarily as an antigen for T lymphocytes. Recent studies, however, indicated that in vitro, GA directly inhibits dendritic cells, a rare but potent type of professional antigen-presenting cell (APC). To investigate whether these in vitro observations are relevant to the actions of GA in vivo, we studied the effects of GA on monocytes, the major type of circulating APC. In a first series of experiments, we investigated the effects of GA on monocyte reactivity in vitro. Monocytes were stimulated with ligands for Toll-like receptor (TLR)-2 (peptidoglycan and lipoteichoic acid), TLR-4 [lipopolysaccharide (LPS)] and TLR-5 (flagellin), as well as two proinflammatory cytokines (interferon-gamma and granulocyte-monocyte colony-stimulating factor). Monocyte activation was measured by induction of the surface markers signalling lymphocytic activation molecule (SLAM), CD25 and CD69 (detected by cytofluorometry), and by production of monocyte-derived tumour necrosis factor (TNF)-alpha (detected by enzyme-linked immunospot assay). GA had a broad inhibitory effect on all measures of monocyte reactivity, regardless of which stimulator was used. It is unlikely that this reflects a simple toxic effect, because monocyte viability and CD14 expression were unaffected. In a second series of experiments, we investigated the properties of monocytes cultured ex vivo from eight GA-treated multiple sclerosis patients, eight untreated multiple sclerosis patients and eight healthy subjects. We found that LPS-induced SLAM expression and TNF-alpha production were significantly reduced in monocytes from GA-treated patients compared with controls. These results demonstrate for the first time that GA inhibits monocyte reactivity in vitro and in vivo, significantly extending the current concept of the mechanism of action of GA.

Adult↗
PubMed1989

A-23187 evoked transmitter release from rabbit pulmonary artery and its inhibition by reactivation of sodium-pump.

1. The spontaneous [3H]-release has been measured from the isolated main pulmonary artery of the rabbit preloaded with [3H]noradrenaline in the presence of uptake blockers (cocaine, 3 x 10(-5) M; corticosterone, 5 x 10(-5) M). 2. The Ca-ionophore A-23187 (3 x 10(-7)-3 x 10(-5) M) increased the outflow of [3H] by a concentration dependent manner. 3. Inhibition of Na+-pump by removal of K+ from the external medium also increased the release of labelled noradrenaline. 4. In the absence of external K+, the applied A-23187 (3 x 10(-6) M; EC50) further increased the release of [3H]. 5. Reactivation of Na+-pump by readmission of K+ (5.9 mM) to the external medium abolished the [3H]-release which had previously been increased in "K+-free" solution. 6. The reactivated Na+-pump significantly inhibited the transmitter releasing action of A-23187. 7. This latter was antagonized by an increase of external Ca2+ (7.5 mM). 8. It is concluded that the reactivated Na+-pump caused re-establishment of Na+-gradient is capable to counteract the Ca-ionophore facilitated Ca2+-influx and release from internal stores, which can be antagonized by excess Ca2+.

Animals↗
PubMedDate not supplied

Inhibition by reactive aldehydes of superoxide anion radical production in stimulated human neutrophils.

alpha,beta-Unsaturated aldehydes were investigated in vitro for their ability to inhibit superoxide anion radical (O2-.) production in stimulated human polymorphonuclear leukocytes (PMN). The aldehydes investigated were (i) trans-4-hydroxynonenal and malonaldehyde (MDA), two toxic lipid peroxidation products; (ii) acrolein and crotonaldehyde, two air pollutants derived from fossil fuel combustion; (iii) trans,trans-muconaldehyde, a putative hematotoxic benzene metabolite. Preincubation of PMN with reactive aldehydes followed by stimulation with the oxygen burst initiator phorbol myristate acetate (PMA) resulted in a dose-dependent inhibition of O2-. production. The concentration at which 50% inhibition (IC50) was observed was 21 microM for acrolein, 23 microM for trans,trans-muconaldehyde, 27 microM for trans-4-hydroxynonenal and 330 microM for crotonaldehyde. A similar inhibitory effect by these aldehydes was observed in digitonin- and concanavalin A-stimulated PMN. MDA inhibited O2-. production in PMA-stimulated PMN by 100% at 10(-2) M but gave no inhibition at 10(-3) M. The standard aldehyde propionaldehyde did not inhibit O2-. production at 10(-3)-10(-6) M. Preincubation of PMN with acrolein in the presence of cysteine completely protected against the inhibitory effect of this reactive aldehyde. The results indicate that the ability of toxic aldehydes to inhibit O2-. production in stimulated PMN correlates directly with their alkylation potential which is a function of the electrophilicity of the beta carbon.

Acrolein↗
PubMed1999

C-reactive protein inhibits chemotactic peptide-induced p38 mitogen-activated protein kinase activity and human neutrophil movement.

Serum levels of the acute-phase reactant, C-reactive protein (CRP), increase dramatically during acute inflammatory episodes. CRP inhibits migration of neutrophils toward the chemoattractant, f-Met-Leu-Phe (fMLP) and therefore acts as an anti-inflammatory agent. Since tyrosine kinases are involved in neutrophil migration and CRP has been shown to decrease phosphorylation of some neutrophil proteins, we hypothesized that CRP inhibits neutrophil chemotaxis via inhibition of MAP kinase activity. The importance of p38 MAP kinase in neutrophil movement was determined by use of the specific p38 MAP kinase inhibitor, SB203580. CRP and SB203580 both blocked random and fMLP-directed neutrophil movement in a concentration-dependent manner. Additionally, extracellular signal-regulated MAP kinase (ERK) was not involved in fMLP-induced neutrophil movement as determined by use of the MEK-specific inhibitor, PD98059. Blockade of ERK with PD98059 did not inhibit chemotaxis nor did it alter the ability of CRP or SB203580 to inhibit fMLP-induced chemotaxis. More importantly, CRP inhibited fMLP-induced p38 MAP kinase activity in a concentration-dependent manner as measured by an in vitro kinase assay. Impressively, CRP-mediated inhibition of p38 MAP kinase activity correlated with CRP-mediated inhibition of fMLP-induced chemotaxis (r = -0.7144). These data show that signal transduction through p38 MAP kinase is necessary for neutrophil chemotaxis and that CRP intercedes through this pathway in inhibiting neutrophil movement.

C-Reactive Protein↗
PubMed1998

Adrenergic reactivity after inhibition of nitric oxide synthesis in the cerebral circulation of awake goats.

The interaction between nitric oxide (NO) and adrenergic reactivity in the cerebral circulation was studied using in vivo and in vitro preparations. Blood flow to one brain hemisphere (cerebral blood flow) was electromagnetically measured in conscious goats, and the effects of norepinephrine, tyramine and cervical sympathetic nerve stimulation were recorded before (control) and after inhibition of NO formation with Nw-nitro-l-arginine methyl ester (l-NAME). The responses to norepinephrine, tyramine and electrical field stimulation were also recorded in segments, 4 mm in length, from the goat's middle cerebral artery under control conditions and after l-NAME. In vivo, l-NAME (10 goats, 47 mg kg-1 administered i.v.) reduced resting cerebral blood flow by 37+/-2%, increased mean systemic arterial pressure by 24+/-3%, reduced heart rate by 35+/-2%, and decreased cerebrovascular conductance by 52+/-2% (all P<0.01). Norepinephrine (0.3-9 microgram), tyramine (50-500 microgram), and supramaximal electrical sympathetic cervical nerve stimulation (1. 5-6 Hz) decreased cerebrovascular conductance, and these decreases were significantly higher after l-NAME than under control conditions, remaining higher for about 48 h after this treatment. Norepinephrine (10-8-10-3 M), tyramine (10-6-10-3 M) and electrical field stimulation (1.5-6 Hz) contracted isolated cerebral arteries, and the maximal contraction, but not the sensitivity, was significantly higher in the arteries treated than in non-treated with l-NAME (10-4 M). Therefore, the reactivity of cerebral vasculature to exogenous and endogenous norepinephrine may be increased after inhibition of NO synthesis. This increase might be related, at least in part, to changes at postjunctional level in the adrenergic innervation of the vessel wall, and it might contribute to the observed decreases in resting cerebral blood flow after inhibition of NO synthesis.

Animals↗
PubMed2005

Estrogen prevents cardiomyocyte apoptosis through inhibition of reactive oxygen species and differential regulation of p38 kinase isoforms.

From human and animal studies, estrogen is known to protect the myocardium from an ischemic insult. However, there is limited knowledge regarding mechanisms by which estrogen directly protects cardiomyocytes. In this report, we employed an in vitro model, in which cultured rat cardiomyocytes underwent prolonged hypoxia followed by reoxygenation (H/R), to study the cardioprotective mechanism of estrogen. 17-beta-estradiol (E2) acting via estrogen receptors inhibited H/R-induced apoptosis of cardiomyocytes. Mitochondrial reactive oxygen species (ROS) generated from H/R activated p38alpha MAPK, and inhibition of p38alpha with SB203580 significantly prevented H/R-induced cell death. E2 suppressed ROS formation and p38alpha activation by H/R and concomitantly augmented the activity of p38beta. Unlike p38alpha, p38beta was little affected by H/R. Dominant negative p38beta protein expression decreased E2-mediated cardiomyocyte survival and ROS suppression during H/R stress. The prosurvival signaling molecule, phosphoinositol-3 kinase (PI3K), has previously been linked to cell survival following ischemia-reperfusion injury. Here, E2-activated PI3K was found to inhibit ROS generated from H/R injury, leading to inhibition of downstream p38alpha. We further linked these signaling pathways in that p38beta was activated by E2 stimulation of PI3K. Thus, E2 differentially modulated two major isoforms of p38, leading to cardiomyocyte survival. This was achieved by signaling through PI3K, integrating cell survival mediators.

Animals↗
PubMed2003

The anti-inflammatory effect of honokiol on neutrophils: mechanisms in the inhibition of reactive oxygen species production.

Reactive oxygen species produced by neutrophils contribute to the pathogenesis of focal cerebral ischemia/reperfusion injury and signal the inflammatory response. We have previously shown that honokiol, an active principle extracted from Magnolia officinalis, has a protective effect against focal cerebral ischemia/reperfusion injury in rats that paralleled a reduction in reactive oxygen species production by neutrophils. To elucidate the underlying mechanism(s) of the antioxidative effect of honokiol, peripheral neutrophils isolated from rats were activated with phorbol-12-myristate-13-acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP) in the presence or absence of honokiol. In this study, we found that honokiol inhibited PMA- or fMLP-induced reactive oxygen species production by neutrophils by three distinct mechanisms: (1) honokiol diminished the activity of assembled-NADPH oxidase, a major reactive oxygen species producing enzyme in neutrophils by 40% without interfering with its protein kinase C (PKC)-dependent assembly; (2) two other important enzymes for reactive oxygen species generation in neutrophils, i.e., myeloperoxidase and cyclooxygenase, were also inhibited by honokiol by 20% and 70%, respectively; and (3) honokiol enhanced glutathione (GSH) peroxidase activity by 30%, an enzyme that triggers the metabolism of hydrogen peroxide (H2O2). These data suggested that honokiol, acting as a potent reactive oxygen species inhibitor/scavenger, could achieve its focal cerebral ischemia/reperfusion injury protective effect by modulating enzyme systems related to reactive oxygen species production or metabolism, including NADPH oxidase, myeloperoxidase, cyclooxygenase, and GSH peroxidase in neutrophils.

Animals↗
PubMed1957

Studies on the Cx-reactive protein. II. Inhibition of the Cx-reactive protein response in rabbits by blockade of the reticulo-endothelial system.

It has been found that normal rabbits respond to the intravenous administration of thorotrast by producing Cx-reactive protein. The amount of Cx-reactive protein produced in response to successive injections of thorotrast progressively diminishes until finally little or no further Cx-reactive protein production can be elicited. The reticulo-endothelial system is believed to be effectively blocked at this point. When such "blocked" rabbits are injected intracutaneously with Cx-reactive protein incorporated in adjuvant they produce significantly less Cx-reactive protein than the amounts elicited by the same stimulus prior to thorotrast treatment. They also fail to develop the characteristic inflammatory reaction seen in the control experiments. In addition, rabbits whose reticulo-endothelial systems are loaded with thorotrast respond to dermal infection with Type I pneumococcus by producing only very small amounts of Cx-reactive protein in comparison with the control animals.

Animals↗
PubMed2006

Carvedilol inhibits platelet-derived growth factor-induced extracellular matrix synthesis by inhibiting cellular reactive oxygen species and mitogen-activated protein kinase activation.

BACKGROUND: Vascular smooth muscle cell (VSMC) proliferation, migration, and extracellular matrix (ECM) synthesis are major pathologic features of chronic allograft vasculopathy. Carvedilol, an anti-hypertensive agent, might be an effective agent for preventing the development and progression of chronic allograft vasculopathy, since it can inhibit VSMC proliferation and migration. The present study was designed to examine the effect of carvedilol on platelet-derived growth factor (PDGF)-induced ECM synthesis in rat VSMCs. Furthermore, we evaluated whether carvedilol inhibits PDGF-induced cellular reactive oxygen species (ROS) and the activation of mitogen-activated protein kinase (MAPK). METHODS: Primary cultured rat VSMCs were stimulated with PDGF-BB (10 ng/ml) in the presence or absence of carvedilol, and the effects of carvedilol were compared with those of ROS or MAPK inhibitors. Fibronectin secretion, proliferating cell nuclear antigen (PCNA) expression, and each MAPK activation were determined by Western blot analysis, total collagen synthesis by [3H]-proline incorporation, and cellular ROS by flow cytometry. RESULTS: PDGF significantly increased PCNA expression, fibronectin secretion, total collagen synthesis, cellular ROS, and MAPK activation in rat VSMCs. Carvedilol at doses that inhibited PDGF-induced cell proliferation, inhibited ECM synthesis, cellular ROS, or subsequent MAPK activation. Structurally different anti-oxidants and extracellular signal-regulated protein kinase or p38 MAPK inhibitor effectively inhibited PDGF-induced fibronectin secretion and total collagen synthesis. CONCLUSIONS: These results suggest that carvedilol inhibits PDGF-induced VSMC proliferation and matrix protein synthesis by inhibiting cellular ROS and the subsequent activation of MAPK. Thus the targeted inhibition of cellular ROS and MAPK might provide an effective therapeutic strategy to treat chronic allograft vasculopathy.

Animals↗
PubMed1996

C-reactive protein inhibits increased pulmonary vascular permeability induced by fMLP in isolated rabbit lungs.

Increased serum concentrations of C-reactive protein (CRP) have previously been shown to downregulate neutrophil (PMN) influx and vascular permeability changes in models of localized inflammation such as alveolitis [R. M. Heuertz, D. Xia, D. Samols, and R. O. Webster, Am. J. Physiol. 266 (Lung Cell. Mol. Physiol. 10): L649-L654, 1994]. Experiments in isolated, buffer-perfused rabbit lungs were used to determine whether CRP attenuates vascular lung injury induced by PMNs stimulated with the chemotactic peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Peritoneal PMN were added to the perfusate of lungs from PMN-depleted rabbits. Stimulation with fMLP produced an immediate and transient rise in pulmonary artery pressure that peaked at 35-40 cmH2O. An increase in permeability occurred 60 min after fMLP, which was marked by a 70% increase (P < 0.05) in filtration coefficient and bronchoalveolar lavage (BAL) protein concentration. CRP pretreatment of PMNs prevented fMLP-induced increases in permeability and significantly reduced the BAL protein below levels in control lungs (P < 0.05). CRP pretreatment of PMNs did not alter the pulmonary arterial pressor response to fMLP and had no effect on the production of leukotrienes, thromboxane, prostacyclin, or superoxide anion induced by fMLP. The mechanism by which CRP protects lung tissue from vascular injury induced by activation of PMNs remains unclear.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Interaction of cromolyn and a muscarinic antagonist in inhibiting bronchial reactivity to sulfur dioxide and to eucapnic hyperpnea alone.

To determine whether the combination of an agent thought to inhibit mediator release (cromolyn) and an agent that inhibits parasympathetic pathways inhibits sulfur dioxide-induced bronchoconstriction more than either agent alone, we measured the bronchomotor response of 9 asthmatic subjects to inhalation of sulfur dioxide after treatment with cromolyn sodium (200 mg by spinhaler), with atropine sulfate (2.0 mg by nebulizer), and with the 2 drugs given together. Then, to determine whether the combination of cromolyn and a parasympathetic antagonist would similarly inhibit bronchoconstriction provoked by a different nonallergic stimulus, we measured the bronchomotor response of another group of asthmatic subjects to eucapnic hyperpnea of dry air at room temperature after treatment with cromolyn (200 mg), with ipratropium bromide (100 and 200 micrograms by metered-dose inhaler), and with cromolyn (200 mg) and ipratropium bromide (200 micrograms) given together. In both studies, we found that the combination treatment provided greater protection than that obtained with either agent alone. The concentration of sulfur dioxide required to cause bronchoconstriction was significantly greater after treatment with the combination of cromolyn and atropine (2.58 ppm, geometric mean) than after cromolyn alone (0.84 ppm), after atropine alone (0.78 ppm), or after placebo (0.43 ppm). Similarly, the rate of ventilation with dry air required to cause bronchoconstriction was significantly greater after treatment with the combination of cromolyn and ipratropium (106 +/- 22 L/min, mean +/- SD) than after cromolyn alone (65 +/- 19 L/min), after 200 micrograms of ipratropium alone (64 +/- 13 L/min), or after placebo (43 +/- 10 L/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗